The JAK (Janus kinase) kinase is a non-receptor tyrosine kinase family in a cell, and the signal generated by the dielectric factor is transmitted through the JAK-STAT signal path. At present, there are four known JAK family members: JAK kinase 1 (JAK1), JAK kinase 2 (JAK2), JAK kinase 3 (JAK3) and Tyrosine kinase 2 (TYK2). The JAK-dependent cell factors participate in the pathogenic process of various inflammations and autoimmune diseases, JAK inhibitors can be widely used for treating various inflammatory diseases.
Baricitinib is a selective JAK1 and a JAK2 inhibitor developed by Lilly and Incyte. In kinase detection, the inhibition strength exhibited by Baricitinib aiming at JAK1 and JAK2 is 100 times higher than that of JAK3. Baricitinib is in clinical trial in the United States at present, and is used for treating rheumatoid arthritis. The chemical name of the medicine is {1-(ethylsulfonyl))-3-[4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl]azetidin-3-yl} ac etonitrile, and the structure is shown as Formula (I).

A certain pharmaceutical activity is of course the basic prerequisite to be fulfilled by a pharmaceutically active agent before same is approved as a medicament on the market. However, there are a variety of additional requirements a pharmaceutically active agent has to comply with. These requirements are based on various parameters which are connected with the nature of the active substance itself. Without being restrictive, examples of these parameters are the stability of the active agent under various environmental conditions, its stability during production of the pharmaceutical formulation and the stability of the active agent in the final medicament compositions.
The pharmaceutically active substance used for preparing the pharmaceutical compositions should be as pure as possible and its stability in long-term storage must be guaranteed under various environmental conditions. This is essential to prevent the use of pharmaceutical compositions which contain, in addition to the actual active substance, breakdown products thereof, for example. In such cases the content of active substance in the medicament might be less than that specified. In addition it is important that the pharmaceutically active substance be non-hygroscopic, stable both to degradation and subsequent changes to its solid form. This is important to facilitate the incorporation of the pharmaceutically active substance into pharmaceutical formulations. If the pharmaceutically active substance is hygroscopic (“sticky”) in the sense that it absorbs water (either slowly or over time) it is almost impossible to reliably formulate the pharmaceutically active substance into a drug as the amount of substance to be added to provide the same dosage will vary greatly depending upon the degree of hydration. Furthermore, variations in hydration or solid form (“polymorphism”) can lead to changes in physico-chemical properties, such as solubility or dissolution rate, which can in turn lead to inconsistent oral absorption in a patient. Preferably, therefore, a pharmaceutically active substance should be only slightly hygroscopic.
Accordingly, chemical stability, solid state stability, “shelf life” and materials handling properties (such as ease of solubilising the compound) of the pharmaceutically active substance are very important factors. In an ideal situation the pharmaceutically active substance and any compositions containing it, should be capable of being effectively stored over appreciable periods of time, without exhibiting a significant change in the physico-chemical characteristics of the active substance such as its activity, moisture content, solubility characteristics, solid form and the like. Further, the drug substance will usually require processing in order to achieve a particle size suitable for inhalation and any crystalline form must be stable during such processing so that the properties of the final product are predictable and reliable. In short, whether or not a compound is suitable for commercialisation as a drug is dependent on finding a form of the compound with a unique combination of properties determined according to the intended route of administration.
Since different crystalline forms of the same compound are significantly different in appearance, solubility, melting point, dissolution rate, bioavailability and the like, pharmaceutical stability, bioavailability and therapeutic effect will be affected. Therefore, the development of new crystalline forms more suitable for use in drug development has great significance.
As is known to those skilled in the art, the presence of new solid polymorphic forms of a known chemical substance is unpredictable. The existence of the polymorphic substance or the number of the polymorphic forms is also unpredictable. In addition, under what conditions to obtain a specific form, and how are the characteristics of the polymorphic form are also unpredictable. Since the properties of each polymorph of the polymorphic forms (e.g., solubility, stability) and thereby causing the difference of use and storage, it is necessary to study all solid forms, including all polymorphic forms to provide drugs with improved storage stability or predictable solubility.
Different crystalline forms cause different solubility and stability of the solid chemical drug, thus affecting the absorption and bioavailability of the drug, and can lead to difference in clinical efficacy. However, there is no report of the crystalline form of the compound of formula (I), and it is necessary to perform a comprehensive polymorph screening of the compound of formula (I) to select the most suitable form for development.
The inventor of the present disclosure has surprisingly found two crystalline forms of the compound of formula (I) and three phosphate crystalline forms in the research process. The crystalline forms in present disclosure have good stability, and the solubility and hygroscopicity meet the requirements for medical use, and the preparation method is simple, the cost is low, which is of great value for the future optimization and development of the drug.